US8940727B2 - Benzazepine compound - Google Patents

Benzazepine compound Download PDF

Info

Publication number
US8940727B2
US8940727B2 US13/504,101 US201013504101A US8940727B2 US 8940727 B2 US8940727 B2 US 8940727B2 US 201013504101 A US201013504101 A US 201013504101A US 8940727 B2 US8940727 B2 US 8940727B2
Authority
US
United States
Prior art keywords
chloro
benzo
methylbenzamide
methylphenyl
carbonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US13/504,101
Other languages
English (en)
Other versions
US20130131045A1 (en
Inventor
Keizo Kan
Tadaaki Ohtani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharmaceutical Co Ltd filed Critical Otsuka Pharmaceutical Co Ltd
Assigned to OTSUKA PHARMACEUTICAL CO., LTD. reassignment OTSUKA PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KAN, KEIZO, OHTANI, TADAAKI
Publication of US20130131045A1 publication Critical patent/US20130131045A1/en
Application granted granted Critical
Publication of US8940727B2 publication Critical patent/US8940727B2/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a benzazepine compound.
  • Patent Literature 1 to 3 several compounds having a vasopressin antagonistic activity have been developed (e.g., Patent Literature 1 to 3 and Non-Patent Literature 1 and 2).
  • Patent Literature 1 to 3 several compounds having a vasopressin antagonistic activity have been developed (e.g., Patent Literature 1 to 3 and Non-Patent Literature 1 and 2).
  • the development of a compound having more excellent vasopressin antagonistic activity is in demand.
  • Patent Literature 3 discloses, in Example 430, compounds exhibiting excellent vasopressin antagonistic activity. Of such compounds, tolvaptan, represented by the following formula, is also disclosed.
  • Patent Literature 3 is silent about the deuterated compound of the present invention.
  • An object of the present invention is to provide a novel benzazepine compound having more excellent vasopressin antagonistic activity than tolvaptan, and having additional benefits, e.g., achieving a further extended pharmacological effective life by producing the compound with high metabolic stability.
  • R 1 may be the same or different and each represents H or D
  • R 2 may be the same or different and each represents H or D
  • R 3 represents a C 1-6 alkyl group, a C 1-6 deuteroalkyl group or a C 1-6 perdeuteroalkyl group,
  • R 4 represents a C 1-6 alkyl group, a C 1-6 deuteroalkyl group or a C 1-6 perdeuteroalkyl group,
  • R 5 may be the same or different and each represents H or D.
  • a benzazepine compound selected from the group consisting of:
  • Item 3 A pharmaceutical composition or a salt thereof comprising, as an active ingredient, the benzazepine compound of Item 1 or 2, and a pharmaceutically acceptable carrier.
  • Item 4 Use of the benzazepine compound or a salt thereof of Item 1 or 2, as a drug.
  • a vasopressin antagonist comprising, as an active ingredient, the benzazepine compound or a salt thereof of Item 1 or 2.
  • Item 6 The pharmaceutical composition according to Item 3, which is for preventing or treating at least one disease selected from the group consisting of hypertension, edema, ascites, heart failure, renal dysfunction, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water-metabolism disorder, renal failure, cerebral infarction, cardiac infarction, and polycystic kidney disease (PKD).
  • SIADH antidiuretic hormone
  • Item 7 The pharmaceutical composition according to Item 3, which is for use as at least one drug selected from the group consisting of vasodilators, antihypertensive agents, water-diuretic agents, platelet aggregation inhibitors, ureotelic agents, anti-heart failure agents, and anti-renal failure agents.
  • Item 8 A method for preventing or treating at least one disease selected from the group consisting of hypertension, edema, ascites, heart failure, renal dysfunction, syndrome of inappropriate secretion of vasopressin (syndrome of inappropriate secretion of antidiuretic hormone: SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water-metabolism disorder, renal failure, cerebral infarction, cardiac infarction, and polycystic kidney diseases (PKD),
  • the method comprising administering the benzazepine compound or a salt thereof of Item 1 or 2, to a human or animal.
  • the present invention provides a benzazepine compound represented by Formula (1) above or a salt thereof.
  • C 1-6 preferably C 1-3 , alkyl groups represented by R 3 and R 4 in Formula (1)
  • R 3 and R 4 in Formula (1) include methyl group, ethyl group, n-propyl group, iso-propyl group, and the like.
  • the C 1-6 , preferably C 1-3 , deuteroalkyl groups represented by R 3 and R 4 in Formula (1) are those in which at least one hydrogen atom of the alkyl group is substituted with a deuterium atom (with the proviso that those in which all of the hydrogen atoms of the alkyl group are substituted with deuterium atoms are excluded).
  • n is an integer of 1 to 6, preferably 1 to 3, and m is an integer of 1 to 2n. More specifically, examples thereof include deuteromethyl group, dideuteromethyl group, deuteroethyl group, dideuteroethyl group, trideuteroethyl group, tetradeuteroethyl group, deuteropropyl group, dideuteropropyl group, trideuteropropyl group, tetradeuteropropyl group, pentadeuteropropyl group, and the like.
  • C 1-6 preferably C 1-3 , perdeuteroalkyl groups represented by R 3 and R 4 in Formula (1)
  • R 3 and R 4 perdeuteroalkyl groups represented by R 3 and R 4 in Formula (1)
  • perdeuteromethyl group perdeuteroethyl group, perdeutero-n-propyl group, perdeutero-iso-propyl group, and the like.
  • the benzazepine compound of the present invention or a salt thereof is produced by a method disclosed in the Reference Examples and Examples, or in accordance with these methods.
  • the benzazepine compound of the present invention obtained by these methods can be separated from the reaction system by a general separation means, and can further be purified.
  • a separation and purification means for example, a distillation method, a recrystallization method, column chromatography, ion-exchange chromatography, gel chromatography, affinity chromatography, preparative thin-layer chromatography, a solvent extraction method, or the like, can be employed.
  • the benzazepine compound of the present invention can form suitable salts.
  • suitable salts include suitable salts of a compound (1) exemplified below.
  • the suitable salts of the compound (1) are pharmacologically acceptable salts.
  • alkali metal salts e.g., sodium salt and potassium salt
  • alkaline earth metal salts e.g., calcium salt and magnesium salt
  • ammonium salts alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, and cesium carbonate)
  • alkali metal hydrogen carbonates e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate
  • alkali metal hydroxides e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide
  • tri(lower)alkylamines e.g., trimethylamine, triethylamine, and N-ethyldiisopropylamine
  • pyridine quinoline, piperidine, imidazol, picoline, dimethylaminopyridine, dimethylaniline, N
  • the benzazepine compound of the present invention also includes those in the form of a solvate with a solvent (e.g., hydrate or ethanol solvate).
  • a solvent e.g., hydrate or ethanol solvate.
  • preferable solvates include hydrate.
  • the compounds of the present invention represented by Formula (1) also naturally include isomers, such as geometrical isomers, stereoisomers, and optical isomers.
  • the compound of Formula (1) and a salt thereof are used in the form of common pharmaceutical preparations.
  • Such pharmaceutical preparations can be prepared by using usually employed diluents and excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants.
  • the form of such pharmaceutical preparations can be selected from various forms, depending on the therapeutic purpose. Typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), and the like.
  • a wide range of carriers known in this field can be used, including, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and like excipients; water, ethanol, propanol, simple syrup, glucose solutions, starch solutions, gelatin solutions, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, and like binders; dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, and like disintegrants; sucrose, stearin, cacao butter, hydrogenated oils, and like disintegration inhibitors; quaternary ammonium base, sodium lauryl sulfate, and like absorption promoters;
  • a wide range of carriers known in this field can be used. Examples thereof include glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc, and other excipients; gum arabic powder, tragacanth powder, gelatin, ethanol, and other binders; laminaran, agar, and other disintegrants; etc.
  • suppositories a wide range of known carriers can be used. Examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.
  • Capsules can be prepared according to a known method, by mixing a usual active ingredient compound with an aforementioned carrier, and encapsulating the resulting mixture into a hard gelatin capsule, soft gelatin capsule, or the like.
  • a solution, emulsion, or suspension is sterilized and preferably made isotonic to blood.
  • Any diluent commonly used in this field can be employed to form the injection. Examples of such diluents include water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, fatty acid esters of polyoxyethylene sorbitan, etc.
  • the pharmaceutical preparation may contain sodium chloride, glucose, or glycerol in an amount sufficient to prepare an isotonic solution, and may contain typical solubilizers, buffers, analgesic agents, etc., and may further contain, if necessary, coloring agents, preservatives, flavors, sweetening agents, etc., and/or other medicines.
  • the amount of the compound of Formula (1) or a salt thereof contained in the pharmaceutical preparation of the present invention is not limited and can be suitably selected from a wide range.
  • the pharmaceutical preparation usually contains the compound or a salt thereof in a proportion of usually about 0.1 to 70 wt %, and preferably about 0.1 to 30 wt %.
  • the route of administration of the pharmaceutical preparation of the present invention is not particularly limited, and the preparation is administered by, for example, a route suitable for the form of the preparation, the patient's age, sex, and other conditions, and the severity of the disease.
  • a route suitable for the form of the preparation for example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are administered orally.
  • Injections are intravenously administered singly or in combination with typical injection transfusions such as glucose solutions, amino acid solutions or the like. Further, injections are singly administered intramuscularly, intracutaneously, subcutaneously, or intraperitoneally, if necessary. Suppositories are administered intrarectally.
  • the dosage of the pharmaceutical preparation of the invention is suitably selected according to the method of use, the patient's age, sex, and other conditions, and the severity of the disease.
  • the amount of active ingredient compound is usually about 0.1 to 10 mg/kg body weight/day. Further, it is desirable that the pharmaceutical preparation in each unit of the administration form contains the active ingredient compound in an amount of about 1 to 200 mg.
  • the benzazepine compound of the present invention exhibits excellent vasopressin antagonistic activity.
  • the specific effects of the vasopressin antagonistic activity include, for example, a vasodilating effect, a hypotensive effect, an inhibitory effect on hepatic glucose release, an inhibitory effect on mesangial cell growth, a water diuretic effect, a platelet aggregation inhibitory effect, an inhibitory effect on vomiting, a ureotelic effect, an inhibitory effect on secretion of factor VIII, a cardiac function increasing effect, an inhibitory effect on mesangial cell contraction, an inhibitory effect on hepatic glucose production, an inhibitory effect on aldosterone secretion, an inhibitory effect on endothelin production, a regulatory effect on renin secretion, a memory modulation effect, a thermoregulatory effect, a regulatory effect on prostaglandin production, etc.
  • a pharmaceutical composition comprising the benzazepine compound of the present invention as an active ingredient is useful as, for example a vasodilator, an antihypertensive agent, a water-diuretic agent, a platelet aggregation inhibitor, a ureotelic agent, an anti-heart failure agent, an anti-renal failure agent, etc.; and is effective in preventing or treating hypertension, edema, ascites, heart failure, renal dysfunction, syndrome of inappropriate secretion of vasopressin (syndrome of inappropriate secretion of antidiuretic hormone: SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water-metabolism disorder, renal failure, cerebral infarction, cardiac infarction, polycystic kidney diseases (PKD), various ischemic diseases, and the like.
  • a vasodilator an antihypertensive agent
  • a water-diuretic agent e.g
  • the benzazepine compound of the present invention has features such as causing few side effects and achieving sustained drug efficacy.
  • Manganese dioxide (2 g) was added to a suspension of N-(4-(7-chloro-5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide (2 g) in dichloromethane (40 mL), and the mixture was refluxed for 7 hours.
  • Citric acid (0.51 g) was added to a solution of ethyl 4-(5-chloro-2-nitrophenyl)-4-(trimethylsilyloxy)butanoate (4.76 g) in ethanol (25 mL) and water (5 mL) and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate.
  • the reaction mixture was stirred at room temperature for 3 days, and water was added thereto, followed by extraction with ethyl acetate.
  • the resulting water layer was subjected to extraction with ethyl acetate again.
  • the ethyl acetate layers obtained were combined, washed with water three times, and dried over anhydrous magnesium sulfate.
  • Triethylamine (0.24 mL) and a solution of the acid chloride prepared above in dichloromethane (5 mL) were sequentially added dropwise to a solution of 5-(tert-butyldimethylsilyloxy)-7-chloro-2,2-dideutero-3,4,5-trihydro-1H-benzo[b]azepine (500 mg) in dichloromethane (50 mL) at 0° C. After stirring at the same temperature for 4 hours, water was added to the reaction mixture, followed by extraction with dichloromethane. The dichloromethane layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate.
  • Manganese dioxide (482 mg) was added to a suspension of N-(4-(7-chloro-5-hydroxy-2,2-dideutero-3,4,5-trihydro-1H-benzo[b]azepine-1-carbonyl)-3-methylphenyl)-2-methylbenzamide (0.25 g) in dichloromethane (50 mL), and the mixture was refluxed for 8 hours. The reaction mixture was cooled and then filtered through Celite.
  • Hexafluorophosphoric 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (3.04 g) was added to a solution of 1-(4-amino-2-methylbenzoyl)-7-chloro-2,3,4-trihydro-1H-benzo[b]azepin-5(2H)-one (2.39 g), 3,4,5,6-tetradeutero-2-trideutero methylbenzoic acid (1.04 g) and triethylamine (1.4 mL, 10 mmol) in dimethylformamide (24 mL). The mixture was then stirred at 65° C. under a nitrogen atmosphere for 4 hours.
  • HeLa cells expressing human Via-receptors (Via-HeLa) cultured in a 12-well plate or HeLa cells expressing human V2-receptors (V2-HeLa) cultured in a 24-well plate were washed with D-PBS twice.
  • [ 3 H]AVP saturation binding assay [ 3 H]AVP with various concentrations (V1a-HeLa; 0.4 nM to 7 nM, V2-HeLa; 0.3 nM to 6 nM) were added to each well containing the reaction mixture (DMEM-0.3% BSA) and allowed to react in the presence and absence of AVP (1 ⁇ M).
  • Binding ratio (%) ( B ⁇ NSB )/( TB ⁇ NSB ) ⁇ 100 (B is the total binding of [ 3 H]AVP in the presence of each compound; NSB is the total binding of [ 3 H]AVP in the presence of unlabeled AVP (1 ⁇ M); and TB is the total binding of [ 3 H]AVP in the absence of unlabeled AVP 1 ⁇ M.)
  • the following reaction system was prepared with reference to the method disclosed by Obach, and that disclosed by Jones et al. (References 1 and 2), and the metabolic stability thereof was evaluated. Note that the human liver microsomes used were purchased from BD Gentest. The test compound was dissolved in DMSO to have a concentration of 10 mM and diluted with acetonitrile in such a manner that its concentration became 100 ⁇ M.
  • a reaction system without a coenzyme was preincubated at 37° C. for 5 minutes, and a coenzyme was then added to start the reaction. After the addition of the coenzyme, the incubation was performed at selected time intervals, i.e., 0, 5, 10, 20, 30 and 60 minutes to extract a portion of the reaction mixture. The extracted reaction mixture was added to an acetonitrile solution containing an internal standard substance and the reaction was then terminated.
  • LC-MS/MS liquid chromatograph tandem mass spectrometer
  • Example 4 The compound of Example 4 exhibited significantly improved metabolic stability compared to tolvaptan.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Otolaryngology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Studio Devices (AREA)
US13/504,101 2009-10-26 2010-10-25 Benzazepine compound Expired - Fee Related US8940727B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2009-245434 2009-10-26
JP2009245434 2009-10-26
PCT/JP2010/068807 WO2011052519A1 (ja) 2009-10-26 2010-10-25 ベンズアゼピン化合物

Publications (2)

Publication Number Publication Date
US20130131045A1 US20130131045A1 (en) 2013-05-23
US8940727B2 true US8940727B2 (en) 2015-01-27

Family

ID=43921941

Family Applications (1)

Application Number Title Priority Date Filing Date
US13/504,101 Expired - Fee Related US8940727B2 (en) 2009-10-26 2010-10-25 Benzazepine compound

Country Status (17)

Country Link
US (1) US8940727B2 (enrdf_load_stackoverflow)
EP (1) EP2495236A4 (enrdf_load_stackoverflow)
JP (1) JP5717645B2 (enrdf_load_stackoverflow)
KR (1) KR20120092139A (enrdf_load_stackoverflow)
CN (3) CN104447555A (enrdf_load_stackoverflow)
AU (1) AU2010312651A1 (enrdf_load_stackoverflow)
BR (1) BR112012009784A2 (enrdf_load_stackoverflow)
CA (1) CA2778756A1 (enrdf_load_stackoverflow)
CO (1) CO6481003A2 (enrdf_load_stackoverflow)
EA (1) EA022253B1 (enrdf_load_stackoverflow)
IL (1) IL219132A0 (enrdf_load_stackoverflow)
IN (1) IN2012DN03343A (enrdf_load_stackoverflow)
MX (1) MX2012004843A (enrdf_load_stackoverflow)
PH (1) PH12012500762A1 (enrdf_load_stackoverflow)
SG (1) SG10201406839VA (enrdf_load_stackoverflow)
WO (1) WO2011052519A1 (enrdf_load_stackoverflow)
ZA (1) ZA201202640B (enrdf_load_stackoverflow)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10562962B2 (en) 2015-07-13 2020-02-18 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019003433A1 (ja) * 2017-06-30 2019-01-03 大塚製薬株式会社 ベンゾアゼピン誘導体
TW201938171A (zh) 2017-12-15 2019-10-01 匈牙利商羅特格登公司 作為血管升壓素Ｖ１ａ受體拮抗劑之三環化合物
HU231206B1 (hu) 2017-12-15 2021-10-28 Richter Gedeon Nyrt. Triazolobenzazepinek
JP6868089B2 (ja) * 2018-12-28 2021-05-12 大塚製薬株式会社 医薬
CN112851583B (zh) * 2021-01-19 2023-09-08 徐州医科大学 新型苯并氮杂䓬类化合物、组合物及其用途

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04321669A (ja) 1991-04-19 1992-11-11 Otsuka Pharmaceut Co Ltd バソプレシン拮抗剤
US5258510A (en) 1989-10-20 1993-11-02 Otsuka Pharma Co Ltd Benzoheterocyclic compounds
JPH0776214B2 (ja) 1989-10-20 1995-08-16 大塚製薬株式会社 ベンゾヘテロ環化合物
US5753677A (en) 1989-10-20 1998-05-19 Otsuka Pharmaceutical Co., Ltd. Benzoheterocyclic compounds
US5856564A (en) 1993-07-21 1999-01-05 Yamanouchi Pharmaceutical Co., Ltd. Condensed benzazepine derivative and pharmaceutical composition thereof
WO2007016431A2 (en) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Novel benzo [d] [1,3]-dioxol derivatives
WO2007143468A2 (en) 2006-06-05 2007-12-13 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted imidazopyridine compounds with hypnotic effects
WO2008049116A2 (en) 2006-10-19 2008-04-24 Auspex Pharmaceuticals, Inc. Substituted indoles
WO2009001968A1 (en) 2007-06-26 2008-12-31 Otsuka Pharmaceutical Co., Ltd. Benzazepine derivatives useful as vasopressin antagonists
WO2009117144A1 (en) 2008-03-20 2009-09-24 Concert Pharmaceuticals, Inc. Benzazepine compounds

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5753677A (en) 1989-10-20 1998-05-19 Otsuka Pharmaceutical Co., Ltd. Benzoheterocyclic compounds
US5258510A (en) 1989-10-20 1993-11-02 Otsuka Pharma Co Ltd Benzoheterocyclic compounds
JPH0776214B2 (ja) 1989-10-20 1995-08-16 大塚製薬株式会社 ベンゾヘテロ環化合物
JP2905909B2 (ja) 1991-04-19 1999-06-14 大塚製薬株式会社 バソプレシン拮抗剤
JPH04321669A (ja) 1991-04-19 1992-11-11 Otsuka Pharmaceut Co Ltd バソプレシン拮抗剤
US5856564A (en) 1993-07-21 1999-01-05 Yamanouchi Pharmaceutical Co., Ltd. Condensed benzazepine derivative and pharmaceutical composition thereof
RU2129123C1 (ru) 1993-07-21 1999-04-20 Яманоути Фармасьютикал Ко., Лтд. Конденсированное производное бензазепина, промежуточное соединение для его получения, фармацевтическая композиция
WO2007016431A2 (en) 2005-07-29 2007-02-08 Concert Pharmaceuticals Inc. Novel benzo [d] [1,3]-dioxol derivatives
JP2009502963A (ja) 2005-07-29 2009-01-29 コンサート ファーマシューティカルズ インコーポレイテッド 新規なベンゾ［ｄ］［１，３］−ジオキソール誘導体
WO2007143468A2 (en) 2006-06-05 2007-12-13 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted imidazopyridine compounds with hypnotic effects
WO2008049116A2 (en) 2006-10-19 2008-04-24 Auspex Pharmaceuticals, Inc. Substituted indoles
WO2009001968A1 (en) 2007-06-26 2008-12-31 Otsuka Pharmaceutical Co., Ltd. Benzazepine derivatives useful as vasopressin antagonists
WO2009117144A1 (en) 2008-03-20 2009-09-24 Concert Pharmaceuticals, Inc. Benzazepine compounds

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Concert Pharmaceuticals et al., Precision Deuterium Chemistry Backgrounder, 2007, pp. 1-6.
Gheorghiade (Effects of Tolvaptan, a Vasopressin Antagonist, in Patients Hospitalized with Worsening Heart Failure, JAMA, Apr. 2004, vol. 291, No. 16). *
Heterocycles, vol. 54, No. 1, pp. 131-138, 2001.
Heterocycles, vol. 54, No. 1, pp. 131-138.
Journal of High Technology Law, vol. X, No. 1, pp. 22-74, 2009.
Journal of High Technology Law, vol. X, No. 1, pp. 22-74.
Kazumi Kondo, et al., "7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1 H-1-benzazepine (OPC-41061): A Potent, Orally Active Nonpeptide Arginine Vasopressin V2 Receptor Antagonist", Bioorganic & Medicinal Chemistry, 1999, pp. 1743-1754, vol. 7, No. 8.
Shoaf, S.E. et al., "Tolvaptan Administration Does Not Affect Steady State Amiodarone Concentrations in Patients With Cardiac Arrhythmias", J Cardiovascular Pharmacology and Therapeutics, vol. 10, No. 3, pp. 165-171, 2005.
Supplementary European Search Report dated Feb. 25, 213 in European Patent Application No. 10826651.1.
U.S. FDA, Application No. NDA 22275, Clinical pharmacology and biopharmaceutics review, pp. 1-60, Aug. 22, 2008.
Yoshitaka Yamamura, et al., "OPC-41061, a Highly Potent Human Vasopressin V2-Receptor Antagonist: Pharmacological Profile and Aquaretic Effect by Single and Multiple Oral Dosing in Rats", The Journal of Pharmacology and Experimental Therapeutics, 1998, pp. 860-867, vol. 287, No. 3.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10562962B2 (en) 2015-07-13 2020-02-18 H. Lundbeck A/S Antibodies specific for hyperphosphorylated tau and methods of use thereof

Also Published As

Publication number Publication date
CN104829531A (zh) 2015-08-12
AU2010312651A1 (en) 2012-05-03
KR20120092139A (ko) 2012-08-20
JP5717645B2 (ja) 2015-05-13
CO6481003A2 (es) 2012-07-16
CN104447555A (zh) 2015-03-25
CN102753530B (zh) 2015-06-17
BR112012009784A2 (pt) 2016-05-17
EA022253B1 (ru) 2015-11-30
CA2778756A1 (en) 2011-05-05
WO2011052519A1 (ja) 2011-05-05
ZA201202640B (en) 2013-06-26
US20130131045A1 (en) 2013-05-23
EP2495236A1 (en) 2012-09-05
IN2012DN03343A (enrdf_load_stackoverflow) 2015-10-23
EP2495236A4 (en) 2013-03-27
SG10201406839VA (en) 2014-12-30
EA201290228A1 (ru) 2012-12-28
IL219132A0 (en) 2012-06-28
JPWO2011052519A1 (ja) 2013-03-21
PH12012500762A1 (en) 2012-11-26
CN102753530A (zh) 2012-10-24
MX2012004843A (es) 2012-05-29

Similar Documents

Publication Publication Date Title
EP2821401B1 (en) Dihydroquinolinone compounds as modulators of the muscarininc m1 receptor
US8940727B2 (en) Benzazepine compound
DE69203955T2 (de) Benzazepinderivate als Vasopressin-Antagonisten.
EP1223170B1 (en) Pyrimidine-5-carboxamide compounds, process for producing the same and use thereof
AU2018208231B2 (en) Imidazopyrazine compound, preparation method therefor and use thereof
US10968198B2 (en) Biaryltriazole inhibitors of macrophage migration inhibitory factor
EP2742045B1 (en) Antibacterial cyclopenta[c]pyrrole substituted 3,4-dihydro-1h-[1,8]naphthyridinones
JP5438007B2 (ja) ＭＤＭ２とｐ５３の間の相互作用の阻害剤
EP4161927B1 (en) Spiro compounds as melanocortin 4 receptor antagonists and uses thereof
US12162858B2 (en) Quinoline derivatives as inhibitors of AXL/MER RTK and CSF1R
AU2012293618B2 (en) Antibacterial homopiperidinyl substituted 3,4 dihydro 1H (1,8)naphthyridinones
CN120025312A (zh) 苯并氮杂卓衍生物
HK1171751A (en) Benzazepine compound
US20100222365A1 (en) Substituted triazole deriviatives as oxytocin antagonists
KR20240121242A (ko) 클라조센탄 디소듐 염, 이의 제조 및 이를 포함하는 약학 조성물
EA048136B1 (ru) Спиросоединения в качестве антагонистов рецептора меланокортина 4 и их применения
EA046014B1 (ru) Средства, модулирующие регулятор трансмембранной проводимости при муковисцидозе

Legal Events

Date Code Title Description
AS Assignment

Owner name: OTSUKA PHARMACEUTICAL CO., LTD., JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KAN, KEIZO;OHTANI, TADAAKI;REEL/FRAME:028367/0188

Effective date: 20120501

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20190127